The long term goal of this project is to gain new and deeper understanding of the determinants of functional action of protein segments in the context of the complete molecular system. The main premise of the research is that these determinants are structurally defined and can be described from a quantitative analysis of the dynamic and structural characteristics of the segments that control structure and function in proteins. The new insights obtained from this approach will, in particular, focus on G-protein coupled receptors (GPCR) and to the interactions between GPCRs and their G-protein partners. The overall aim of these applications is to significantly increase our insights into the fundamental molecular mechanisms that are the basis of the broad spectrum of responses observed as structure function relationships. Particular attention will be focused on understanding how protein segments in the GPCRs respond to ligand binding and how and why these elements respond differently to distinctive classes of substances. The class of drugs with hallucinogenic properties will be of particular interest because molecular based insights into how they illicit responses in GPCRs that are different from those of nonhallucinogenic compounds may provide clues for developing therapeutic agents that mitigate or neutralize the effects of hallucinogens. The research proposed in this project applies the methods of computational biophysics, such as molecular modeling and simulation, combined with a number of newly developed theoretical and computational tools, to probe the origin of the differentiated receptor response to different ligands. However, the computational experiments to be carried out are designed to be subject to experimental verification, which forms an integral part of the proposed research. The new computational approaches available for this project were designed to i) extend the structural models of GPCRs to include functionally important protein segments that are missing in current models, ii) to identify and analyze characteristics of protein architecture that are related to function, iii) to calculate and evaluate electrostatic properties of GPCRs, focusing on drug dependent differences that may lead to different receptor responses, and iv) to combine the new insights gained from i) to iii) to study distinctive activation mechanisms in GPCRs by using drug/GPCR models as the basis for comparing changes in the response of molecular segments that are part of the molecular mechanism that triggers GPCRs to achieve their function.